1. The Arthur and Sonia Labatt Brain Tumor Research Centre, University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Canada
2. Program in Developmental Biology, University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Canada
3. Division of Neurosurgery, University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Canada
4. Department of Pediatric Laboratory Medicine, University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Canada
5. Integrative Biology Program, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Canada
6. Ontario Cancer Institute and University of Toronto, 610 University Avenue, Toronto, M5G 2M9, Canada
7. Division of Neurosurgery, St Michael's Hospital and University of Toronto, 30 Bond Street, Toronto M5B 1W8, Canada

Correspondence to: Peter B. Dirks^1,2,3 Email: peter.dirks@sickkids.ca

The cancer stem cell (CSC) hypothesis suggests that neoplastic clones are maintained exclusively by a rare fraction of cells with stem cell properties^{1, 2}. Although the existence of CSCs in human leukaemia is established^{3, 4}, little evidence exists for CSCs in solid tumours, except for breast cancer⁵. Recently, we prospectively isolated a CD133⁺ cell subpopulation from human brain tumours that exhibited stem cell properties in vitro⁶. However, the true measures of CSCs are their capacity for self renewal and exact recapitulation of the original tumour^{1, 2, 7}. Here we report the development of a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo. Only the CD133⁺ brain tumour fraction contains cells that are capable of tumour initiation in NOD-SCID (non-obese diabetic, severe combined immunodeficient) mouse brains. Injection of as few as 100 CD133⁺ cells produced a tumour that could be serially transplanted and was a phenocopy of the patient's original tumour, whereas injection of 10⁵ CD133^- cells engrafted but did not cause a tumour. Thus, the identification of brain tumour initiating cells provides insights into human brain tumour pathogenesis, giving strong support for the CSC hypothesis as the basis for many solid tumours⁵, and establishes a previously unidentified cellular target for more effective cancer therapies.

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